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Chlorobenzene
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Acute Exposure Guideline Levels

PREFACE

Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals.

AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows:

AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory

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1 This document was prepared by the AEGL Development Team composed of J.J.A. Muller and Peter Bos (both from RIVM, The Dutch National Institute of Public Health and the Environment), Julie M. Klotzbach (Syracuse Research Corporation), Chemical Manager Marinelle Payton (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001).



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3 Chlorobenzene1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distin- guished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory 1 This document was prepared by the AEGL Development Team composed of J.J.A. Muller and Peter Bos (both from RIVM, The Dutch National Institute of Public Health and the Environment), Julie M. Klotzbach (Syracuse Research Corporation), Chemical Manager Marinelle Payton (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifi- cally valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 82

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83 Chlorobenzene effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure concentra- tions that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen- sory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold concentrations for the general public, including susceptible subpopula- tions, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic re- sponses, could experience the effects described at concentrations below the cor- responding AEGL. SUMMARY Chlorobenzene is a flammable liquid with a high vapor pressure and a wa- ter solubility of 50 milligrams per liter (mg/L) at 20°C. It is used as a solvent and in the production of nitrochlorobenzene and intermediates for the synthesis of dyestuffs, pharmaceuticals, and products for the rubber and plastic industries. Chlorobenzene has an aromatic, almond-like odor. The odor threshold is 0.050 mg/L in water and is 0.2-1.8 ppm in air, although a value of 62 ppm has also been reported for air. The toxicity database on chlorobenzene is poor. Information often had to be obtained from descriptions in reviews and summaries, and some older litera- ture could not be obtained (e.g., Rozenbaum et al. [1947]). Human data include to two kinetic studies with volunteers. Animal data included studies on terato- genicity, reproductive toxicity, and mortality. A few studies with experimental animals addressing central nervous system (CNS) depression were reviewed, but were difficult to interpret. AEGL-1 values are based on kinetic studies with volunteers. Effects in subjects exposed to chlorobenzene at 60 ppm for 7 h (with a 1-h break after 3 h) are indicative of slight CNS depression (drowsiness, heavy head, and headache) and local irritation (Ogata et al. 1991), and are considered evidence of discom- fort. These effects were not observed is subjects exposed at 10 ppm for 8 h

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84 Acute Exposure Guideline Levels (Knecht and Woitowitz 2000). Thus, 10 ppm was chosen as a conservative point of departure for the derivation of AEGL-1 values. Because human data are used, an interspecies uncertainty factor of 1 was used. Despite the fact that only a few subjects were tested, an uncertainty factor of 1 for intraspecies variability was considered appropriate because of the conservatism of the point of departure already provides a margin of safety. (The point of departure of 10 ppm was ob- tained from a repeated-exposure study, and effects observed at 60 ppm were rather slight.) No information about the time dependency of the effects at 10 or 60 ppm is available. Because the effects at 60 ppm include irritation and CNS effects, the 8-h AEGL-1 value of 10 ppm is considered appropriate for all time points. Furthermore, Knecht and Woitowitz (2000) reported that chlorobenzene concentrations in blood reached a steady-state level within 1 h. There are no adequate human data for deriving AEGL-2 values. Some studies with experimental animals report subtle CNS effects, but the relevance of these effects to humans is difficult to interpret. The effects reported by Fran- tik et al. (1994) and De Ceaurriz et al. (1983) are considered effects below those defined by AEGL-2. A more appropriate study is the one by UBTL (1978), in which rats and guinea pigs experienced narcosis and effects that would impair ability to escape. A no-effect concentration of 2,990 ppm for 30 min was se- lected as the point of departure for calculating AEGL-2 values. An interspecies uncertainty factor of 3 was applied, because data were comparable for rats and guinea pigs, suggesting no large interspecies differences, and the critical effect is CNS depression. The concentration of chlorobenzene in the brain is probably related directly to inhalation rate. Therefore, humans probably require higher external exposures than rodents to obtain a similar concentration of chloroben- zene in the blood or brain. Experience with anesthetic gases shows that interin- dividual variability in CNS depression caused by these gases is generally not greater than a factor of 2 or 3. Therefore, an intraspecies uncertainty factor of 3 was used. A combined uncertainty factor of 10 was considered appropriate be- cause a larger factor would result in AEGL-2 values below 60 ppm, which a concentration shown to cause only minor effects in humans. The 30-min AEGL- 2 was 300 ppm. The 30-min value was extrapolated to 10-min and 1-h values using the equation Cn × t = k, with default values of n = 1 for extrapolation to 1 h and n = 3 for extrapolation to 10 min. The 4- and 8-h AEGL-2 values were set equal to the 1-h value because chlorobenzene concentrations in blood reach a steady-state within 1 h and elimination is rapid. Furthermore, time scaling would result in 4- and 8-h AEGL-2 values that conflict with human data (Ogata et al. 1991). For the derivation of AEGL-3 values, several mortality studies were found, but most were only available as summaries in other publications and could not be judged on their merits. Bonnet et al. (1979, 1982) reported a 6-h LC50 (lethal concentration, 50% lethality) of 2,965 ppm for male rats and a 6-h LC50 of 1,886 ppm for mice. No deaths were reported in rats or guinea pigs ex- posed to chlorobenzene at concentrations of up to 7,970 ppm for 30 min (UBTL 1978). Data in rats and guinea pigs reported by UBTL (1978) provide the most

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85 Chlorobenzene appropriate point of departure for AEGL-3 derivation. A total uncertainty factor of 10 was applied on the same basis it was applied in the derivation of the AEGL-2 values, and time scaling was performed the same as was done for the AEGL-2 values. AEGL-3 values are consistent with the AEGL-2 values and are supported by the 6-h LC01 of 1,873 ppm calculated from the probit equation re- ported by Bonnet et al. (1982). AEGL values for chlorobenzene are presented in Table 3-1. 1. INTRODUCTION Chlorobenzene is a flammable liquid with a high vapor pressure and a wa- ter solubility of 50 mg/L at 20°C. It is commercially produced by the chlorina- tion of benzene in the presence of a catalyst (ATSDR 1990). Chlorobenzene is used as a solvent and in the production of nitrochlorobenzene and intermediates for the synthesis of dyestuffs, pharmaceuticals, and products for the rubber and plastic industries (BUA 1990). The production volume of chlorobenzene in 1992 was 231 million pounds in the United States (EPA 1995). More current informa- tion on production volumes was not available. Chlorobenzene has an aromatic, almond-like odor. The odor threshold for chlorobenzene in water is 0.050 mg/L and in air is 0.2-1.8 ppm (Verschueren 1983). Odor thresholds for chlorobenzene have been reported as low as 0.2 ppm and as high as 62 ppm (Ruth 1986). Chemical and physical properties for chlorobenzene are presented in Table 3-2. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality No data were available. TABLE 3-1 Summary of AEGL Values for Chlorobenzene End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 10 ppm 10 ppm 10 ppm 10 ppm 10 ppm No irritant or CNS (nondisabling) (47 (47 (47 (47 (47 effects (Ogata et al. mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) 1991; Knecht and Woitowitz 2000) AEGL-2 430 ppm 300 ppm 150 ppm 150 ppm 150 ppm Narcosis (UBTL (disabling) (2,021 (1,410 (705 (705 (705 1978) mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 1,100 ppm 800 ppm 400 ppm 400 ppm 400 ppm No mortality in (lethal) (5,170 (3,760 (1,880 (1,880 (1,880 rats or guinea pigs mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (UBTL 1978)

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86 Acute Exposure Guideline Levels TABLE 3-2 Chemical and Physical Properties for Chlorobenzene Parameter Value Reference CAS registry no. 108-90-7 Synonyms Monochlorobenzene; benzene chloride; phenylchloride; MCB; chlorobenzol Chemical formula C6H5Cl Molecular weight 112.56 Physical state Liquid ATSDR 1990 Color Colorless ATSDR 1990 Odor Aromatic, almond-like ATSDR 1990 Melting point -45.6°C ATSDR 1990 Boiling point 132°C ATSDR 1990 3 Liquid density (water = 1) 1.1058 g/cm ATSDR 1990 Solubility in water 500 mg/L at 20°C ATSDR 1990 Vapor pressure 8.8 mm Hg at 20°C ATSDR 1990 Flammability 1.8-9.6% ATSDR 1990 Lower explosive limit 1.3% NIOSH 2011 3 Conversion factors 1 mg/m = 0.22 ppm ATSDR 1990 1 ppm = 4.7 mg/m3 2.2. Nonlethal Toxicity 2.2.1. Case Reports Several reviews including those of ACGIH (1991) and Hellman (1993) cited reports in which inhalation and oral exposure to chlorobenzene are de- scribed as having caused drowsiness, incoordination, and unconsciousness, as well as irritation of the eyes and respiratory tract. However, exposure concentra- tions were not specified. Ruth (1986) reported that 205 ppm was an irritating concentration of chlorobenzene, but the source of that information was not provided. 2.2.2. Experimental Studies In a study investigating urinary metabolites of chlorobenzene, subjects were asked to report subjective effects of the exposure (Ogata et al. 1991). Vol- unteers were exposed to chlorobenzene at 60.2 ± 3.9 ppm for 3 h in the morning

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87 Chlorobenzene and 4 h in the afternoon, with a 1-h break between exposures. The concentra- tions were determined by gas chromatography and were reported to be constant within a 5% range. All of the volunteers complained of a disagreeable odor and drowsiness. Three had a heavy feeling in the head or headache, two had a throb- bing pain in the eyes, and one had a sore throat. No information was given about the onset of these complaints. Chlorobenzene did not affect pulse rates or sys- tolic and diastolic pressure. Flicker fusion frequency values (frequency at which successive flashes are seen as continuous) were reduced significantly from 39.1 to 35.9 cycles/second at the end of the 3-h exposure. No further effect was seen in the afternoon. The significance of this finding is difficult to interpret. Eight volunteers were exposed to chlorobenzene at 10 ppm for 8 h per day for five consecutive days to determine the relationship between chlorobenzene and urinary concentrations of its metabolites 4-chlorocatechol and chlorophenols (Knecht and Woitowitz 2000). None of the subjects complained of irritant or CNS effects (U. Knecht, Justus Liebig University Giessen, Germany, personal commun., 2005). 2.2.3. Occupational and Epidemiologic Studies The potential consequences of occupational exposure to chlorobenzene are described in a report by Izmerov et al. (1988). These cases are not included in the chapter because concentrations of chlorobenzene in those studies were un- clear and coexposure to other chemicals was possible. 2.3. Neurotoxicity Izmerov et al. (1988) described changes in electroencephalogram (EEG) readings as “evident on an individual basis” during exposure to chlorobenzene and as near-term and long-term effects. The specific changes were not de- scribed. On the basis of changes in electrical brain activity, 0.2 mg/m3 (0.044 ppm) appeared to be a threshold concentration (exposure duration unknown), and 0.1 mg/m3 (0.022 ppm) was a no-effect concentration. No further details were provided in the Izmerov report, and the original publications were not available. Therefore, these results are considered supplementary information. 2.4. Summary No information is available on the acute lethality of chlorobenzene in hu- mans. Chlorobenzene can be irritating to the eyes and respiratory tract, and signs of CNS effects (drowsiness, heavy feeling in the head, and headache) have been report in people exposed at 60 ppm for 7 h. Odor might have interfered with subjective complaints of irritation. No complaints of irritation were described in another study in which volunteer were exposed to chlorobenzene at 10 ppm for 8 h/day for 5 days.

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88 Acute Exposure Guideline Levels 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality The acute lethality data on chlorobenzene in laboratory animals is pre- sented in Table 3-3. TABLE 3-3 Acute Lethality Data on Chlorobenzene in Laboratory Animals Concentration Exposure Species (sex) Effect Reference (ppm) Duration Single exposure Rats (male) 2,965 6h LC50 Bonnet et al. 1982 Rats (or mice) 4,400 2h LC100 Rozenbaum et al. 1947 Guinea pigs 7,970 30 min No mortality UBTL 1978 Rats 22,000 3.5 h 2 of 3 died Eastman Kodak Co. 1994 Rats 9,000 6h 2 of 3 died Eastman Kodak Co. 1994 Rats 7,970 30 min No mortality UBTL 1978 Mice (female) 1,886 6h LC50 Bonnet et al. 1979 Mice 7,832 2h LC84 Sanotsky and Ulanova 1975 4,070 2h LC50 2,244 2h LC16 Related exposures Rat (two- 450 6 h/d, 7 d/wk No mortality Nair et al. 1987 generation study) for up to 17 wk Rabbits (pregnant) 3,000 6 h/d for 13 d Mortality John et al. 1984 1,000 No mortality Rats (pregnant) 3,000 6 h/d for 10 d Mortality John et al. 1984 1,000 No mortality Rats 248 7 h/d, 5 d/wk No mortality Dilley 1977 for 24 wk

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89 Chlorobenzene 3.1.1. Rabbits A description of a study by Rozenbaum et al. (1947) was obtained from a report by ATSDR (1990), because the original publication could not be ob- tained. Rabbits (sex and number not specified) exposed to chlorobenzene (head only or whole body) at 550-660 ppm for 4 h died after 2 weeks, but no effects were observed at 110-220 ppm. Rabbits were also reported to have died 2 weeks after exposure to chlorobenzene at 537 ppm for 2 h. These results contrast with findings in other studies. For example, repeated exposure of 32 male rabbits to chlorobenzene at 248 ppm for up to 24 weeks did not increase mortality (Dilley 1977). In addition, no mortality was observed in a teratogenicity study of rabbits exposed at 1,000 ppm (6 h/day for 10 days), but deaths were observed at 3,000 ppm (John et al. 1984) (see Section 3.3 for further details of this study). 3.1.2. Guinea Pigs Groups of five guinea pigs per sex were exposed (whole body) to chloro- benzene at mean (± standard deviation [SD]) analytic concentrations of 2,990 ± 53, 5,850 ± 1,350, or 7,970 ± 355 ppm for 30 min, and were observed for 14 days. No deaths were observed at any concentration (UBTL 1978). 3.1.3. Rats Bonnet et al. (1982) determined the 6-h LC50 for chlorobenzene in male Sprague-Dawley rats. Twelve rats per concentration were exposed (whole body) and observed for 14 days. Nominal test concentrations were not provided. Ac- tual concentrations were determined using gas chromatography, but information on the exposure concentrations was limited to a graph on log scale. It was esti- mated that the lowest concentration tested in rats was approximately 2,000 ppm and was associated with 8% mortality. The LC50 was 2,965 ppm (95% confi- dence interval [CI]: 2,787-3,169 ppm), with a regression line of probit = -33 + 10.9 logC (the paper presented a positive intercept [+33] but the data indicate that it should be -33). Hypotony, stereotypy, somnolence, tremor, and muscle contractions were observed during exposure. A 2-h LC100 value of 4,400 ppm for rats was determined by Rozenbaum et al. (1947, as reported by BUA 1990). However, according to ATSDR (1990), this study was performed in mice. The original publication could not be re- trieved to clarify the discrepancy. The following statement was found in a submission to the U.S. Environ- mental Protection Agency (Eastman Kodak Co 1994): “Acute exposure to 22,000 ppm for 3½ h killed 2/3 rats in 2½ h while 9,000 ppm for 6 h killed 2/3 rats in 3 h.” A reference to unpublished data from the Eastman Kodak Company was cited, but the original study was not available.

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90 Acute Exposure Guideline Levels Groups of five rats per sex were exposed (whole body) to chlorobenzene at mean (± SD) analytic concentrations of 2,990 ± 53, 5,850 ± 1,350, or 7,970 ± 355 ppm for 30 min, and animals were observed for 14 days. No deaths were observed at any concentration (UBTL 1978). Repeated exposure of 32 male rats to chlorobenzene at 248 ppm for up to 24 weeks did not result in mortality (Dilley 1977). In addition, no mortality was observed in a two-generation study (450 ppm, 6 h/day, 7 days/week for 17 weeks) (Nair et al. 1987) or in a rat developmental toxicity study (1,000 ppm, 6 h/day for 10 days) (John et al. 1984). However, in the latter study, increased mortality was observed at 3,000 ppm (John et al. 1984). 3.1.4. Mice Bonnet et al. (1979) determined the 6-h LC50 of chlorobenzene in female mice (OF1). Groups of 25 mice were exposed to chlorobenzene (whole body) and observed for 14 days. Nominal test concentrations were not provided. Ac- tual concentrations were determined using gas chromatography. The analytic concentrations were 90-100% of the nominal concentrations. No details on the exposure concentrations were provided other than a graph on log scale. It was estimated that the lowest concentration tested was approximately 1,500 ppm and caused approximately 20% mortality. The LC50 was 1,886 ppm (95% CI: 1,781 -1,980 ppm), with a regression line of probit = -17.06 + 6.734 logC (the paper presented a positive intercept [+17.06] but the data indicate that it should be -17.06). Izmerov et al. (1988) described a study by Sanotsky and Ulanova (1975) that found a 2-h LC50 of 4,070 ppm, an LC16 of 2,244 ppm, and an LC84 of 7,832 ppm for chlorobenzene in mice. Izmerov also reported that another study re- ported that exposure to chlorobenzene at 2,200 ppm (duration unknown) failed to kill mice, but that at 4,400 ppm three of four mice died. Neither of the pri- mary studies could be obtained. A 2-h LC100 value of 4,400 ppm for mice was reported by Rozenbaum et al. (1947, as cited by ATSDR 1990). However, according to BUA (1990), this study was performed in rats. The original publication could not be retrieved to clarify the discrepancy. 3.2. Nonlethal Toxicity The acute nonlethal effects of chlorobenzene in laboratory animals are summarized in Table 3-4. 3.2.1. Guinea Pigs Groups of five guinea pigs per sex were exposed (whole body) to chloro- benzene at mean (± SD) analytic concentrations of 2,990 ± 53, 5,850 ± 1,350, or

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91 Chlorobenzene 7,970 ± 355 ppm for 30 min, and were observed for 14 days. No deaths were observed at any concentration. At 2,990 ppm, slight ocular and nasal irritation was observed, but none of the animals were judged to have an impaired ability to escape. At the next higher concentration of 5,850 ppm, all guinea pigs suf- fered from narcosis and were judged to have impaired ability to escape. No deaths occurred at the highest concentration but ataxia occurred within 10 min and narcosis was evident after 15 min (UBTL 1978). TABLE 3-4 Acute Nonlethal Effects of Chlorobenzene in Laboratory Animals Species Concentration Exposure (sex) (ppm) Duration Effect Reference Guinea pigs 2,990 30 min Slight ocular and nasal UBTL 1978 irritation; no impaired ability to escape. 5,850 30 min Narcosis in all guinea pigs. 7,970 30 min Ataxia within 10 min and narcosis within 15 min. Rats 2,990 30 min Slight ocular and nasal UBTL 1978 irritation; no impaired ability to escape. 5,850 30 min Narcosis in most rats. 7,970 30 min Ataxia at 10 min and narcosis within 25 min. Rats (male) 1,500 8 h/d for Reduction in auditory-evoked Rebert et al. 1995 5d response. 1,000 No effect. Rats (male) 611 4h Shortening of the tonic Frantik et al. 1994 extension of the hind limbs by 37.5% after electrical stimulation. Mice (male) 1,054 5 min RD50 for sensory irritation. De Ceaurriz et al. 1981 Mice 75 3 h, once No effect on host defense. Aranyi et al. 1986 or for 5 d Mice (female) 610 2h Increased velocity of the tonic Frantik et al. 1994 extension of the hind limbs by 30% after electrical stimulation. Mice (male) 650 4h Decrease in immobility in De Ceaurriz et the “behavioral despair” al. 1983 swimming test by 2.

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92 Acute Exposure Guideline Levels 3.2.2. Rats Groups of five rats per sex were exposed (whole body) to chlorobenzene at mean (± SD) analytic concentrations of 2,990 ± 53, 5,850 ± 1,350, or 7,970 ± 355 ppm for 30 min, and were observed for 14 days. No deaths were observed at any concentration. At 2,990 ppm, slight ocular and nasal irritation was observed but none of the animals were judged to suffer from impaired ability to escape. At the next higher concentration of 5,850 ppm, most rats suffered from “narco- sis” and were judged to have impaired ability to escape; the animals recovered quickly after exposure ended. No deaths occurred at the highest concentration, but ataxia was present at 10 min and narcosis was evident in all animals after 25 min of exposure (UBTL 1978). Frantik et al. (1994) investigated the relative neurotoxicity of several sol- vents. Groups of four adult male rats (albino, specific pathogen free) were ex- posed at least three concentrations of chlorobenzene (analytic purity) or to am- bient air. Inhalation exposure was performed in a dynamic system for 4 h, and concentrations were measured by gas chromatography. The actual exposure concentrations were not specified. Most animals were tested three or four times at intervals of 3 weeks. Immediately after exposure, the animals received a short electrical pulse through ear electrodes. The duration of subsequent tonic exten- sion of the hind limbs was determined. This parameter was shown to be the most sensitive and consistent. The study authors calculated the concentration required to induce a 37.5% change in the neurologic response (decrease in duration of the tonic extension from 8 to 5 seconds). A 37.5%-effect concentration of 611 ppm (90% CI: 538-684 ppm) was reported for chlorobenzene. The slope was 0.061%/ppm. A 37.5% response corresponds, according to the study authors, to a concentration that does not influence normal locomotor activity or induce be- havioral excitation, so it may be considered a sensitive neurologic end point. Rebert et al. (1995) studied the effect of chlorobenzene on the auditory system of rats. Groups of eight or nine male Long Evans rats were exposed (whole body) at target concentrations of chlorobenzene of 500-2,400 ppm for 8 h per day for 5 days. Analytic concentrations determined by gas chromatography were within 10% of the target concentrations. Auditory function was assessed 3-13 days after exposure using the brainstem auditory-evoked response (integrated ampli- tude) elicited by 16-kilohertz (kHz) tone pips over a range of 25-95 decibels (dB), with 10 dB increments. The average response over 55-85 dB was compared with controls. A reduction in the integrated amplitude of the response was found in animals exposed at 2,000 ppm or 2,400 ppm in one experiment and at approxi- mately 1,500 or 2,000 ppm in another (estimated from a figure) but not at 500 or 1,000 ppm (estimated from a figure). For one of the experiments, the effect was still present 4 weeks after exposure. Although it was not a subject in the Rebert et al. (1995) study, it is known that exposure to other organic solvents can result in permanent hearing loss from the destruction of cochlear hair cells. A reduction in body weight gain was observed at 2,000 and 2,400 ppm. No information was available on body weights of animals exposed at 1,500 ppm or less. Other effects

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109 Chlorobenzene Grilli, S., G. Arfellini, A. Colacci, M. Mazzullo, and G. Prodi. 1985. In vivo and in vitro covalent binding of chlorobenzene to nucleic acids. Jpn. J. Cancer Res. 76(8):745- 751. Haworth, S., T. Lawlor, K. Mortelmans, W. Speck, and E. Zeiger. 1983. Salmonella mutagenicity test results for 250 chemicals. Environ. Mutagen. (suppl. 1):3-142. Hayes, W.C., T.S. Gushaw, K.A. Johnson, T.R. Hanley, J.H. Ouellette, and J.A. John. 1982. Monochlorobenzene: Inhalation Teratology Study in Rats and Rabbits. Dow Chemical Company, Midland, MI (as cited in NTP 1985). Hellman, B. 1993. NIOH and NIOSH Basis for an Occupational Health Standard: Chlorobenzene. DHHS (NIOSH) 93-102. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, Na- tional Institute for Occupational Safety and Health, Cincinnati, OH. January 1993 [online]. Available: http://www.cdc.gov/niosh/docs/93-102/pdfs/93-102.pdf [ac- cessed Feb. 29, 2012]. IPCS (International Programme on Chemical Safety). 1991. Chlorobenzenes Other than Hexachlorobenzene. Environmental Health Criteria 128. Geneva, Switzerland: Health Organization [online]. Available: http://www.inchem.org/documents/ehc/ ehc/ehc128.htm [accessed Feb. 27, 2012]. Izmerov, N.F., N.M. Vasilenko, N.N. Semiletkina, and L.A. Timofiyevskaya. 1988. Chlorobenzenes (Chlorobenzene, Dichlorobenzene, Trichlorobenzene). Scientific Reviews of Soviet Literature of Toxicity and Hazards of Chemicals No. 108. Mos- cow: GKNT (Centre for International Projects). John, J.A., W.C. Hayes, T.R. Hanley, Jr., K.A. Johnson, T.S. Gushow, and K.S. Rao. 1984. Inhalation teratology study on monochlorobenzene in rats and rabbits. Toxi- col. Appl. Pharmacol. 76(2):365-373. Keskinova, D. 1968. The action of dimethylcyclodiazomethane in chlorobenzene solu- tions on the mutation process in Actinomycetes antibioticus-400. Sov. Gen. 4:1082-1085 (as cited in NTP 1985). Khalil, A.M., and M.M.T. Odeh. 1994. Genetic toxicology of benzene and its derivatives in rat bone marrow cell cultures. Toxicol. Environ. Chem. 45(3-4):157-166. Knecht, U., and H.J. Woitowitz. 2000. Human toxicokinetics of inhaled monochloroben- zene: Latest experimental findings regarding re-evaluation of the biological toler- ance value. Int. Arch. Occup. Environ. Health 73(8):543-554. Krewet, E., G. Müller, and K. Norpoth. 1989. The excretion of chlorophenylmercapturic acid, chlorophenols and a guanine adduct in the urine of chlorobenzene-treated rats after phenobarbital pretreatment. Toxicology 59(1):67-79 (as cited in Arbetslivs- insinstitutet 2003). Lawlor, T., S. Hanworth, and P. Voytek. 1979. Evaluation of the genetic activities of nine chlorinated phenols, seven chlorinated benzenes and three chlorinated hexanes [abstract]. Environ. Mutagen. 1:143(A) (as cited in NTP 1985). Loveday. K.S., M.H. Lugo, M.A. Resnick, B.E. Anderson, and E. Zeiger. 1989. Chro- masome aberration and sister chromatid exchange tests in chinese hamster ovary cells in vitro: II. Results with 20 chemicals. Environ. Mol. Mutagen. 13(1):60-94 (as cited in BUA 1990). McGregor, D.B., A. Brown, P. Cattanach, I. Edwards, D. McBride, C. Riach. and W.J. Caspary. 1988. Responses of the L5178Y tk+/tk- mouse lymphoma cell forward mutation assay: III. 72 coded chemicals. Environ. Mol. Mutagen. 12(1):85-154 (as cited in BUA 1990).

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110 Acute Exposure Guideline Levels Mihail, F. 1984. Monochlorbenzol, Untersuchung auf Hautsensibilisierende Wirkung bei Meerschweinchen. BAYER AG, Institut für Toxikologie, Bericht Nr. 13057, Wuppertal-Elberfeld 19. 11. 1984 (as cited in BUA 1990) Mohtashamipur, E., R. Triebel, H. Straeter, and K. Norpoth. 1987. The bone marrow clastogenicity of eight halogenated benzenes in male NMRI mice. Mutagenesis 2(2):111-113 (as cited in ICPS 1991). Monsanto Company. 1976. Litton Bionetics Mutagenicity Evaluation of Bio-75-86-CP 5535 (WGK): Monochlorobenzene. Office of Pesticides and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC. TSCA Sec 8(d) Submission 8DHQ-1078-0214(1) (as cited in EPA 1985). MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). 2004. Nationale MAC-lijst 2004: Chloorbenzeen. Den Haag: SDU Uitgevers [online]. Available: http://www. lasrook.net/lasrookNL/maclijst2004.htm [accessed Feb. 27, 2012]. Nair, R.S., J.A. Barter, R.E. Schroeder, A. Knezevich, and C.R. Stack. 1987. Two- generation reproduction study with monochlorobenzene vapor in rats. Fundam. Appl. Toxicol. 9(4):678-686. NIOSH (National Institute for Occupational Safety and Health). 1994. Documentation for Immediately Dangerous to Life or Health Concentrations (IDLHs): Chlorobenzene. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Cincinnati, OH [online]. Available: http://www.cdc.gov/niosh/idlh/108907.html [accessed Feb. 28, 2012]. NIOSH (National Institute for Occupational Safety and Health). 2011. NIOSH Pocket Guide to Chemical Hazards: Chlorobenzene. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupa- tional Safety and Health, Cincinnati, OH [online]. Available: http://www.cdc.gov/ niosh/npg/npgd0121.html [accessed Feb. 28, 2012]. NRC (National Research Council). 1993. Guidelines for Developing Community Emer- gency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press. NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: Na- tional Academy Press. NTP (National Toxicology Program). 1985. Toxicology and Carcinogenesis Studies of Chlorobenzene in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report No. 261. NIH 86-2517. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Toxicology Program, Research Triangle Park, NC [online]. Available: http://ntp.niehs.nih.gov/ntp/htdo cs/LT_rpts/tr261.pdf [accessed Feb. 27, 2012]. Ogata, M., and Y. Shimada. 1983. Differences in urinary monochlorobenzene metabolites between rats and humans. Int. Arch. Occup. Environ. Health 53(1):51-57. Ogata, M., T. Taguchi, N. Hirota, Y. Shimada, and S. Nakae. 1991. Quantitation of uri- nary chlorobenzene metabolites by HPLC: Concentrations of 4-chlorocatechol and chlorophenols in urine and of chlorobenzene in biological specimens of subjects exposed to chlorobenzene. Int. Arch. Occup. Environ. Health 63(2):121-128. Prasad, I. 1970. Mutagenic effects of the herbicide 3,4-dichloropropionanilide and its degradation products. Can. J. Microbial. 16(5):369-372. Prasad, I., and D. Pramer. 1968. Mutagenic activity of some chloroanilines and chloro- benzenes. Genetics 20:212-213.

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111 Chlorobenzene Rebert, C.S., R.W. Schwartz, D.J. Svendsgaard, G.T. Pryor, and W.K. Boyes. 1995. Combined effects of paired solvents on the rat's auditory system. Toxicology 105(2-3):345-354. Reid, W.D. 1973. Mechanism of renal necrosis induced by bromobenzene or chloroben- zene. Exp. Mol. Path. 19(2):197-214. Reid, W.D., and G. Krishna. 1973. Centrolobular hepatic necrosis related to covalent binding of metabolites of halogenated aromatic hydrocarbons. Exp. Mol. Pathol. 18(1):80-99. Rozenbaum, N.D., R.S. Blekh, S.N. Kremneva, S.L. Ginzburg, and L.V. Pozhatiskii. 1947. Use of chlorobenzene as a solvent from the standpoint of industrial hygiene [in Russian]. Gig. Sanit. 12(1):21-24 (as cited in ATSDR 1990, BUA 1990). Ruth, J.H. 1986. Odor thresholds and irritation levels of several chemical substances: A review. Am. Ind. Hyg. Assoc. J. 47(3):A142-A151. Sanotsky, I.V., and L.P. Ulanova. 1975. Criteria of Safety in Assessing the Danger of Chemical Compounds [in Russian]. Moscow: Meditsina (as cited in Izmerov et al. 1988). Shelby, M.D., G.L. Erexson, G.J. Hook, and R.R. Tice. 1993. Evaluation of a three- exposure mouse bone marrow micronucleus protocol: Results with 49 chemicals. Environ. Mol. Mutagen. 21(2):160-179. Shimada, Y. 1988a. Studies on monochlorobenzene poisoning: Part III. Distribution of monochlorobenzene in the organs of pregnant mice and transfer to the fetus through the placenta: Comparison with trichloroethylene and 1, 1, 1-trichloroethane. Oka- yama Igakkai Zasshi 100(1-2):147-153. Shimada, Y. 1988b. Studies on monochlorobenzene poisoning: Part II. Distribution of monochlorobenzene among the organs of mice. Okayama Igakkai Zasshi 100(1- 2):135-146. Shimada, T., C.A. McQueen, and G.M. Williams. 1983. Study of Effects on Cultured Liver Cells of Three Chlorinated Benzenes. Final Report. Prepared by American Health Foundation, for Chemical Manufacturer Association. Shimizu, M., Y. Yasui, and N. Matsumoto. 1983. Structural specificity of aromatic com- pounds with special reference to mutagenic activity in Salmonella typhimurium: A series of chloro-or fluoro-nitrobenzene derivatives. Mutat. Res. 116(3-4):217-238. Simmon, V.F., E.S. Riccio, and M.V. Peirce. 1979. In Vitro Microbiological Genotoxicity Assays of Chlorobenzene, m-Dichlorobenzene, o-Dichlorobenzene and p-Dichlorobenzene. Report No. EPA 560/1979 SRI/002. Contract No 68-02- 2947. Menlo Park, CA: SRI International (as cited in EPA 1985 and BUA 1990). Suberg, H. 1983. Chlorbenzol rein, Prüfung auf primär reizende/ätzen de Wirkung am Kaninchenauge. Briefbericht der Bayer AG, Institut für Toxikologie (as cited in BUA 1990) Sullivan, T.M., G.S. Born, G.P. Carlson, and W.V. Kessler. 1983. The pharmacokinetics of inhaled chlorobenzene in the rat. Toxicol. Appl. Pharmacol. 71(2):194-203. UBTL (Utah Biomedical Test Laboratory). 1978. Utah Biomedical Test Laboratory Re- port on NIOSH Sponsored Inhalation Study for IDLH Values (Final Report) with Cover Letter Dated 10/22/91. Submitted by Shell Oil Company to U.S. Environ- mental Protection Agency, Washington, DC. EPA Document No. TSCATS 88- 920000156. Microfiche No. OTS 0534605. Vaghef, H., and B. Hellman. 1995. Demonstration of chlorobenzene-induced DNA dam- age in mouse lymphocytes using the single cell gel electrophoresis assay. Toxicol- ogy 96(1):19-28.

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112 Acute Exposure Guideline Levels Valencia, R. 1982. Drosophila Sex Linked Recessive Lethal Test on Monochlorobenzene. Prepared by University of Wisconsin, Madison, WI. Submitted by Bioassay Sys- tem Corporation, Woburn, MA, to U.S. Environmental Protection Agency, Wash- ington, DC. EPA Document 40-8320545. Microfiche No. OTS0511274. Verschueren, K. 1983. Pp. 350-359, 712-717 in Handbook of Environmental Data on Organic Chemicals, 2nd Ed. New York: Van Nostrand Reinhold Company (as cited in ATSDR 1990). Williams, G.M., H. Mori, and C.A. McQueen. 1989. Structure-activity relationships in the rat hepatocyte DNA-repair test for 300 chemicals. Mutat. Res. 221(3):263-286 (as cited in BUA 1990).

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113 Chlorobenzene APPENDIX A DERIVATION OF AEGLS VALUES FOR CHLOROBENZENE Derivation of AEGL-1 Values Key studies: Ogata, M., and Y. Shimada. 1983. Differences in urinary monochlorobenzene metabolites between rats and humans. Int. Arch. Occup. Environ. Health 53(1):51-57. Knecht, U., and H.J. Woitowitz. 2000. Human toxicokinetics of inhaled monochlorobenzene: Latest experimental findings regarding re-evaluation of the biological tolerance value. Int. Arch. Occup. Environ. Health 73(8):543-554. Toxicity end point: Slight CNS effects (drowsiness, heavy feeling in the head, and headache) and local irritation at 60 ppm (7 h with a 1-h break after 3 h) and no effects at 10 ppm (8 h/day for 5 days). The latter concentration was used as the point of departure. Time scaling: None, because chlorobenzene concentrations in blood reach a steady-state level within 1 h. Uncertainty factors: 1 for interspecies differences 1 for intraspecies variability Calculations: 10-min AEGL-1: Set equal to 8-h AEGL-1 value of 10 ppm 30-min AEGL-1: Set equal to 8-h AEGL-1 value of 10 ppm 1-h AEGL-1: Set equal to 8-h AEGL-1 value of 10 ppm 4-h AEGL-1: Set equal to 8-h AEGL-1 value of 10 ppm 8-h AEGL-1: 10 ppm Derivation of AEGL-2 Values Key study: UBTL (Utah Biomedical Test Laboratory). 1978. Utah Biomedical Test Laboratory Report on NIOSH Sponsored Inhalation Study for IDLH

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114 Acute Exposure Guideline Levels Values (Final Report) with Cover Letter Dated 102291. Submitted by Shell Oil Company to U.S. Environmental Protection Agency, Washington, DC. EPA Document No. TSCATS 88-920000156. Microfiche No. OTS 0534605. Toxicity end point: Narcosis in rats and guinea pigs. Time scaling: 2,990 ppm for 30 min was extrapolated across time periods using the equation Cn × t = k, with default values of n = 1 for extrapolation to 10-min and n = 3 for extrapolation to 1-h values. The 4- and 8-h values were set equal to the 1-h value because a steady-state chlorobenzene concentration in blood is reached within 1 h and for reasons of consistency with human data. C3 × t = k: k = (2,990 ppm)3 × 30 min = 8.02 × 1011 ppm-min C1 × t = k: k = 2,990 ppm × 30 min = 89,700 ppm-min Uncertainty factors: 3 for interspecies differences 3 for intraspecies variability Calculations: [(8.02 × 1011 ppm-min) ÷ 10 min]1/3 ÷ 10 = 430 10-min AEGL-2: ppm (rounded) 30-min AEGL-2: 2,990 ppm ÷ 10 = 300 ppm (rounded) 1-h AEGL-2: (89,700 ppm-min ÷ 60 min) ÷ 10 = 150 ppm 4-h AEGL-2: Set equal to 1-h AEGL-2 value of 150 ppm 8-h AEGL-2: Set equal to 1-h AEGL-2 value of 150 ppm Derivation of AEGL-3 Values Key study: UBTL (Utah Biomedical Test Laboratory). 1978. Utah Biomedical Test Laboratory Report on NIOSH Sponsored Inhalation Study for IDLH Values (Final Report) with Cover Letter Dated 102291. Submitted by Shell Oil Company to U.S. Environmental Protection Agency, Washington,

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115 Chlorobenzene DC. EPA Document No. TSCATS 88-920000156. Microfiche No. OTS 0534605 Toxicity end point: No mortality in rats or guinea pigs. Time scaling: 7,970 ppm for 30 min was extrapolated across time periods using Cn × t = k, with default values of n = 1 for extrapolation to 10-min and n = 3 for extrapolation to 1-h values. The 4- and 8-h values were set equal to the 1-h value because a steady- state chlorobenzene concentration in blood is reached in 1 h and for reasons of consistency with AEGL-2 values. C3 × t = k: k = (7,970 ppm)3 × 30 min = 1.52 × 1013 ppm-min C1 × t = k: k = 7,970 ppm × 30 min = 239,100 ppm-min Uncertainty factors: 3 for interspecies differences 3 for intraspecies variability Calculations: [(1.52 × 1013 ppm-min) ÷ 10 min]1/3 ÷ 10 = 1,100 10-min AEGL-3: ppm (rounded) 30-min AEGL-3: 7,970 ppm ÷ 10 = 800 ppm (rounded) 1-h AEGL-3: (239,100 ppm-min ÷ 60 min) ÷ 10 = 400 ppm (rounded) 4-h AEGL-3: Set equal to 1-h AEGL-3 value of 400 ppm 8-h AEGL-3: Set equal to 1-h AEGL-3 value of 400 ppm

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116 Acute Exposure Guideline Levels APPENDIX B CATEGORY PLOT FOR CHLOROBENZENE Chemical Chemical Toxicity - All Chlorobenzene 100000,0000 10000,0000 Human - No effect Human Discomfort Human - Disabling 1000,0000 ppm Animal - No effect AEGL - 3 Animal - Discomfort Animal Disabling AEGL - 2 100,0000 Animal - Some Lethality Animal - Lethal AEGL AEGL - 1 10,0000 1,0000 0 60 120 180 240 300 360 420 480 Minutes FIGURE B-1 Category plot of animal and human data and AEGL values for chloro- benzene.

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117 Chlorobenzene APPENDIX C ACUTE EXPOSURE GUIDELINE LEVELS FOR CHLOROBENZENE Derivation Summary for Chlorobenzene AEGL-1 VALUES 10 min 30 min 1h 4h 8h 10 ppm 10 ppm 10 ppm 10 ppm 10 ppm (47 mg/m3) (47 mg/m3) (47 mg/m3) (47 mg/m3) (47 mg/m3) Key references: Study 1: Ogata, M., and Y. Shimada. 1983 Differences in urinary monochlorobenzene metabolites between rats and humans. Int. Arch. Occup. Environ. Health 53(1):51-57. Study 2: Knecht, U., and H.J. Woitowitz. 2000. Human toxicokinetics of inhaled monochlorobenzene: Latest experimental findings regarding re-evaluation of the biological tolerance value. Int. Arch. Occup. Environ. Health 73(8):543-554. Test species/Strain/Number: Humans, 4 subjects (study 1), 8 subjects (study 2) Exposure route/Concentrations/Durations: Study 1: inhalation, 60 ppm, 7-h exposure with a 1-h break after 3 h; Study 2: inhalation, 10 ppm, 8 h/day for 5 days Effects: Study 1: slight CNS effects (drowsiness, heavy feeling in the head, and headache) and local irritation at 60 ppm; Study 2: no effects at 10 ppm. End point/Concentration/Rationale: No discomfort effects at 10 ppm Uncertainty factors/Rationale: Total uncertainty factor: 1 Interspecies: 1, data are from a human study Intraspecies: 1, effects at 60 ppm were very slight Modifying factor: None Animal-to-human dosimetric adjustment: Not relevant Time scaling: None. No information on time dependency is available in the studies, but the observed effects do not indicate a strong time dependency; this is also supported by absorption data. Data adequacy: The key studies were evaluations of the kinetics of chlorobenzene, and were not designed to determine toxicity. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 430 ppm 300 ppm 150 ppm 150 ppm 150 ppm (2,021 mg/m3) (1,410 mg/m3) (705 mg/m3) (705 mg/m3) (705 mg/m3) Key reference: UBTL (Utah Biomedical Test Laboratory). 1978. Utah Biomedical Test Laboratory Report on NIOSH Sponsored Inhalation Study for IDLH Values (Continued)

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118 Acute Exposure Guideline Levels AEGL-2 VALUES Continued 10 min 30 min 1h 4h 8h 430 ppm 300 ppm 150 ppm 150 ppm 150 ppm (2,021 mg/m3) (1,410 mg/m3) (705 mg/m3) (705 mg/m3) (705 mg/m3) (continued) (Final Report) with Cover Letter Dated 102291. U.S. EPA/OPTS Public Files OTS0534605. Submitted by Shell Oil Company to U.S. Environmental Protection Agency, Washington, DC. EPA Document No. TSCATS 88-920000156. Microfiche No. OTS 0534605. Test species/Strain/Number: Rats and guinea pigs, strains unknown, five per sex per species. Exposure route/Concentrations/Durations: Inhalation, 2,990, 5,850, or 7,970 ppm for 30 min; 14-day observation. Effects: 2,990 ppm: Slight ocular and nasal irritation 5,850 ppm: Narcosis and impaired ability to escape 7,970 ppm: No deaths; ataxia and narcosis End point/Concentration/Rationale: No narcosis at 2,990 ppm for 30 min; no animals suffered from impaired ability to escape. Uncertainty factors/Rationale: Total uncertainty factor: 10 (a larger uncertainty factor would lead to AEGL-2 values that conflict with human data) Interspecies: 3, data were comparable for rats and guinea pigs suggesting no large interspecies differences, and the critical effect is CNS depression. Intraspecies: 3, interindividual variability for CNS depression by comparable gases generally will not be greater than a factor of 2 or 3. Modifying factor: None Animal-to-human dosimetric adjustment: None Time scaling: Cn × t = k; default values of n = 3 for 10-min value and n = 1 for 60-min value. AEGL-2 values for 4 and 8 h are set equal to the 1-h value because chlorobenzene concentrations in blood reach a steady-state within 1 h and its elimination is rapid. Time scaling would result in 4- and 8-h AEGL-2 values that would conflict with human data. Data adequacy: Only one study (30-min exposures at three concentrations) aimed at identifying an immediately dangerous to life and health value. AEGL-3 VALUES 10 min 30 min 1h 4h 8h 1,100 ppm 800 ppm 400 ppm 400 ppm 400 ppm (5,170 mg/m3) (3,760 mg/m3) (1,880 mg/m3) (1,880 mg/m3) (1,880 mg/m3) Key reference: UBTL (Utah Biomedical Test Laboratory). 1978. Utah Biomedical Test Laboratory Report on NIOSH Sponsored Inhalation Study for IDLH Values (Continued)

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119 Chlorobenzene AEGL-3 VALUES Continued 10 min 30 min 1h 4h 8h 1,100 ppm 800 ppm 400 ppm 400 ppm 400 ppm (5,170 mg/m3) (3,760 mg/m3) (1,880 mg/m3) (1,880 mg/m3) (1,880 mg/m3) (Final Report) with Cover Letter Dated 102291. Submitted by Shell Oil Company to U.S. Environmental Protection Agency, Washington, DC. EPA Document No. TSCATS 88-920000156. Microfiche No. OTS 0534605 Test species/Strain/Number: Rats and guinea pigs, strains unknown, five per sex per species. Exposure route/Concentrations/Durations: Inhalation, 2,990, 5,850, or 7,970 ppm for 30 min; 14-day observation. Effects: 2,990 ppm: Slight ocular and nasal irritation 5,850 ppm: Narcosis and impaired ability to escape 7,970 ppm: No deaths; ataxia and narcosis End point/Concentration/Rationale: No deaths after 30-min exposure at 7,970 ppm. Uncertainty factors/Rationale: Total uncertainty factor: 10 (a larger factor would lead to AEGL-3 values that would conflict with AEGL-2 values) Interspecies: 3, data were comparable for rats and guinea pigs suggesting no large interspecies differences, and the critical effect is CNS depression. Intraspecies: 3, interindividual variability for CNS depression by comparable gases generally will not be greater than a factor of 2 or 3. Modifying factor: None Animal-to-human dosimetric adjustment: None Time scaling: Cn × t = k; default values of n = 3 for 10-min value and n = 1 for 1-h value. AEGL-3 values for 4- and 8-h are set equal to the 1-h value because chlorobenzene concentrations in blood reach a steady-state within 1 h and its elimination is rapid. Furthermore, time scaling would result in 4- and 8-h AEGL-3 values that would conflict with AEGL-2 values and human data. Data adequacy: Sufficient